JP2804558B2 - Method for producing 2-chloro-5-chloromethylpyridine - Google Patents

Abstract

The invention relates to a multistage process for preparing 2-chloro-5-chloromethylpyridine, in which the sequence of reactions is as follows: <IMAGE> (Stufe = stage> but where the second and the third stage or the third and the fourth stage or the second, third and fourth stage can be carried out directly in one reaction step without isolating the intermediates. <??>Compound (I) is a known intermediate for preparing insecticides.

Description

The present invention relates to a novel process for preparing 2-chloro-5-chloromethylpyridine used as an intermediate for the production of known insecticides.

2-Chloro-5-chloromethylpyridine is converted to the corresponding acid chloride in a complex multi-stage process, i.e., by converting 2-chloropyridine-5-carboxylic acid to the corresponding acid chloride with thionyl chloride.
Obtained when the acid chloride is esterified, if appropriate, with ethanol and subsequently reduced with sodium boranate to produce the hydroxymethyl compound, and the hydroxyl group of the side chain is finally replaced by chlorine with thionyl chloride. [See, eg, US Pat. No. 4,576,629; J. Org. Chem. 34 , 3545]
(1969); J. Heterocycl. Chem
m.) 16 , 333-337 (1979)].

However, the starting compound 2-chloropyridine-5-
High price of carboxylic acid and sodium borate reducing agent,
Furthermore, the latter problem of the safety of generating hydrogen in the course of the reaction is a disadvantage of the above-mentioned process and hinders large-scale industrial practice.

Further, 2-chloro-5-chloromethylpyridine is 2-chloro-5-chloromethylpyridine.
It is known to be obtained when chloro-5-methylpyridine is reacted with elemental chlorine [see, for example, German Patent Publication No. 3,630,046]. However, a disadvantage of this method is that the chlorination is interrupted early in the time before the reaction is complete, in order to avoid the reaction from proceeding uniformly and thus avoiding the formation of substantial amounts of polychlorinated by-products. [See, also, Lorosuppa Patents 9,212 and 65,358]. The resulting mixture is difficult to separate and gives products of unsatisfactory purity.

This time formula (I) Of 2-chloro-5-chloromethylpyridine of the formula (II) Is reacted with phosphorus pentachloride, if appropriate in the presence of thionyl chloride and, if appropriate, in the presence of a diluent, and then the resulting compound of the formula (III) 3-trichloromethylpyridine of the formula (IV) R-OM (IV) in the second stage, if appropriate in the presence of a diluent, wherein R represents alkyl and M is an alkali metal cation. With the alkali metal alkoxide of formula (V) Wherein R has the meaning given above, in a third stage, if appropriate, with water in the presence of a catalytic acid, and then the resulting formula (VI) Wherein R has the meaning given above, in a fourth stage hydrogenation with molecular hydrogen in the presence of a hydrogenation catalyst and, if appropriate, of a diluent, and finally obtained Formula (VII) Wherein R has the meaning given above, when the pyridylmethanol is reacted in a fifth stage with a chlorinating agent in the presence of a diluent and, if appropriate, in the presence of a reaction aid, in a high yield and It has been found that it can be obtained in high purity. However, in this method, steps 2 and 3,
Alternatively, it is also possible to carry out Step 3 and Step 4 or any of Steps 2, 3 and 4 directly by a one-step reaction without isolating the intermediate (so-called “one-port reaction”).

The overall reaction sequence of the present invention must be classified as quite surprising and unpredictable to one skilled in the art. In addition, the combination of five reaction steps makes the whole process new and worthy of the invention.

Thus, for example, the reaction of nicotinic acid with phosphorus pentachloride or with phosphorus pentachloride in the presence of thionyl chloride according to step 1 of the process of the invention is a straightforward reaction of the desired 3-trichloromethylpyridine of formula (III) and It would not be expected to produce in very high yields. The reason, on the other hand, is that phenylphosphine chloride, which is very reactive, complicated to manufacture and difficult to handle, is required as a chlorinating agent or a reaction aid to achieve high yields. (See U.S. Pat. No. 4,634,771 in this regard), while studies by the applicant have shown that the direct direct reaction of nicotinic acid with phosphorus pentachloride [in this regard, Hedron Letters (Tetrah
edron Letters) 25 , 5693-5696 (1984)] by itself or in the presence of diluents, but only in yields of up to 5% of the desired trichloromethylpyridine compounds of the formula (III). It is because it is publicly known.

Another unexpected aspect is that in the reaction of a 2-alkoxy-5-pyridylmethanol of formula (VII) with a chlorinating agent such as phosphorus oxychloride or phosgene according to step 5 of the process of the invention, one chlorine group is converted to a hydroxyl group. And the alkoxy group would be exchanged simultaneously.
The reason for this, on the other hand, is that the "Vilsmeier-Hark conditions", which are largely unsuitable for large-scale industrial operation, due to past technology
(I.e. using phosphorus oxychloride in the presence of large amounts of dimethylformamide, which results in considerable wastewater during treatment)
It is necessary to convert 2-methoxypyridine to 2-chloropyridine, since it is known that phosphorus oxychloride in the absence of dimethylformamide does not cause any reaction. . Further
In yields of 40% or less, the reaction produces only very impure products and the purification by chromatography is complicated [see, in this connection, synthesis (Sy
nthesis) 1984 , 743-745]. On the other hand, it is known that comparable reactions with thionyl chloride only result in exchange at the hydroxyl group, leaving the ether function unmodified [cf.
No. 3,855].

Finally, steps 2 and 3 of the method of the invention, or steps 3 and 4 of the method of the invention, or steps 2, 3 and 4 of the method of the invention can be carried out directly without isolation of intermediates. It was also unexpected that it could be done. The reason is that such a "one-pot reaction" only gives satisfactory results in exceptional cases, especially if it covers more than two reaction steps, a usual considerable yield loss And / or requires a complicated reaction operation.

A particular advantage of the reaction procedure according to the invention which has to be emphasized is that the starting material nicotinic acid is an inexpensive starting material which can be produced on a large industrial scale, and furthermore that all reactions are selective. And that it can be carried out in high yields using readily available reagents under conditions which can be used under industrial conditions, and that the above-mentioned changes without isolating certain intermediates are reasonable And economical synthesis.

For example, if nicotinic acid is used as the starting compound, thionyl chloride and phosphorus pentachloride as reactants in step 1, sodium methoxide as reactant in step 2, dilute hydrochloric acid as reaction aid in step 3, hydrogenation in step 4 Using activated carbon on palladium as catalyst and phosgene in the presence of dibutylformamide as chlorinating agent in step 5, the reaction course of the process according to the invention can be represented by the following equation: Suitable diluents for performing step 1 of the process of the present invention are inert organic solvents. Benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene or phosphorus oxychloride are particularly preferably used. It is also possible to carry out step 1 of the invention essentially directly without using a diluent.

When carrying out step 1 of the process according to the invention, the reaction temperatures can be varied within a substantial range. Generally this method is 80 ~
It is carried out at a temperature of 180 ° C, preferably between 110 and 160 ° C.

When carrying out step 1 of the process according to the invention, 2 to 4 mol of phosphorus pentachloride per mol of nicotinic acid of the formula (II), or in order to avoid a substantial excess of phosphorus pentachloride, 2 mol (in this process the starting nicotinic acid is converted to the corresponding acid chloride hydrochloride) and then 1-2 mol of phosphorus pentachloride are used. It is also possible to prepare phosphorus pentachloride directly from a suitable amount of phosphorus trichloride and an equal amount of chlorine in a reaction vessel. In the course of the reaction, it is advisable to continuously distill off the generated phosphorus oxychloride.

The purified product of the formula (III) can be isolated by distillation, but it is also possible to use the crude product for further reactions.

Formula (IV) provides a general definition of the alkali metal alkoxide required as a starting material for performing step 2 of the process of the present invention. In this formula (IV), R is preferably straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, especially methyl,
Represents ethyl, isopropyl, i-butyl or sec-butyl.

M preferably represents a sodium or potassium cation, especially a sodium cation.

The alkali metal alkoxide of the formula (IV) is a known compound. If necessary, they may be prepared directly from alkali metal hydroxides and the corresponding alkoxides.

Suitable diluents for carrying out step 2 of the process of the invention are also inert solvents. The lower alkyl alcohols having the same alkyl groups as the alkali metal alkoxides of the formula (IV) used as reactants, especially methanol, ethanol, isopropanol or isobutanol, are particularly preferably used.

When carrying out step 2 of the process according to the invention, the reaction temperatures can be varied within a substantial range. Generally, this step is
It is carried out at a temperature between 120 ° C., preferably between 20 and 90 ° C.

When carrying out step 2 of the process of the invention, 3 of formula (III)
3.0-15.0 mol, preferably 3.0-6.0 mol, of alkali metal alkoxide of the formula (IV) per mol of trichloromethylbenzene are generally used. The reaction is carried out in a known manner, and the reaction product is worked up and isolated (see Examples). Suitable catalytic acids for carrying out step 3 of the process according to the invention are dilute inorganic or organic acids. Dilute aqueous hydrochloric acid, sulfuric acid, formic acid or acetic acid is preferably used as the reaction medium. The reaction can be carried out in pure water as a reaction medium without using a catalytic acid.

When carrying out step 3 of the process according to the invention, the reaction temperatures can be varied within a substantial range. Generally, this step is
It is carried out at a temperature between -100 ° C, preferably between 20-80 ° C.

When carrying out stage 3 of the process according to the invention, 10.0 to 50.0 mol of water and, if appropriate, 0.01 to 10.0 mol of catalytic acid are used per mol of pyridine ether acetal of the formula (V). The reaction is carried out according to a conventional method, and the reaction product is processed and isolated (see Production Examples).

Suitable hydrogenation catalysts for carrying out step 4 of the process according to the invention are customary noble metal catalysts, noble metal oxide catalysts or Raney catalysts, if appropriate on a suitable support such as activated carbon, alumina or silicon dioxide. Things. Palladium on activated carbon or Raney nickel is particularly advantageously used.

Suitable diluents for performing step 4 of the process of the present invention are inert organic solvents. These are especially ethers such as diethyl ether, dioxane, tetrahydrofuran or ethyl glycol dimethyl ether or ethyl glycol diethyl ether, alcohols such as methanol,
Ethanol, propanol, butanol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, or acids such as acetic acid.

When carrying out step 4 of the process according to the invention, the reaction temperatures can be varied within a substantial range. Generally, this step is
It is carried out at a temperature of 150150 ° C., preferably 20-100 ° C.

Step 4 of the process of the invention is carried out at atmospheric pressure or at elevated or reduced pressure. In general, the process is carried out at a pressure of from 0.01 to 200 bar, preferably from 0.1 to 100 bar.

When carrying out step 4 of the process according to the invention, 1.0 to 20.0 mol, preferably 1.0 to 2 mol, per mol of pyridine aldehyde of the formula (VI)
1.0-5.0 mol hydrogen and 0.0001-1.0 mol, preferably
0.01-0.1 mol of hydrogenation catalyst is generally used. The reaction is carried out, processed and isolated according to the usual customary methods (cf. Examples).

Suitable chlorinating agents for carrying out step 5 of the process of the invention are, in particular, phosphorus pentachloride, phosphorus oxychloride or phosgene, as well as mixtures of these compounds.

Step 5 of the process according to the invention can be carried out without the addition of a diluent or in the presence of a suitable diluent. These are, in particular, aliphatic, cycloaliphatic or aromatic, optionally halogenated hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or tetrachloride. Contains carbon.

If appropriate, step 5 of the process according to the invention can be carried out in the presence of a suitable reaction auxiliary. Suitable reaction auxiliaries are tertiary amines such as triethylamine, N, N-dimethylaniline, pyridine or N, N-dimethylaminopyridine, and also catalytic amounts of formamides such as N, N-dimethylformamide or N, N-dibutylformamide. Or inorganic metal chlorides such as magnesium chloride or lithium chloride.

When carrying out step 5 of the process according to the invention, the reaction temperatures can be varied within a substantial range. Generally this method is 20 ~
It is carried out at a temperature of 200C, preferably 60-150C.

When carrying out step 5 of the process according to the invention, 1.0 to 10.0 mol, preferably 1.0 to 5.0 mol, of chlorinating agent and, if appropriate, 0.01 to 3.0 mol, preferably 0.1 to 2.0 mol, per mol of pyridylmethanol of the formula (VII) Molar reaction auxiliaries are generally used.

Especially when a gaseous chlorinating agent is used, the reaction process can be monitored by thin-layer chromatography. The reaction product is processed in a conventional manner.

When carrying out the "one-pot process", water and, if necessary, an appropriate amount of a catalytic acid are added at room temperature to the reaction mixture obtained in step 2 of the process of the invention and present as a solution ^{* in} methanol, then the mixture Need Stirred for 0.5 to 20 hours at an appropriate temperature ^** and water The hydrogenation catalyst and, if necessary, a further solvent are added to the reaction mixture, the mixture is hydrogenated in the customary manner at the required temperature and pressure, and when the hydrogenation is complete, the mixture is neutralized and the insoluble components And the liquid is treated by distillation (cf. Examples).

The compound 2-chloro-5-chloromethylpyridine of the formula (I) is a known compound, which can be prepared according to the process of the invention and which is, for example, an insecticide nitromethylene compound (see, for example, European Patent No. 163,855). No. 1,
92,060, 259,738, and 254,859).

Example Stage 1: 123.1 g (1 mol) of nicotinic acid were added to 250 ml of thionyl chloride over 10 minutes. During this step the temperature of the mixture rose to 50 ° C. When the addition is complete, the mixture is
Stirring at 15 ° C. for 15 minutes, excess thionyl chloride was subsequently distilled off under reduced pressure. Then 275 g (2 mol) of phosphorus trichloride were added and a total of 140 g (2 mol) of dry chlorine gas was passed over 2 hours. During this time the temperature of the mixture rose to 70 ° C. Thereafter, the mixture was heated to 150 ° C. for 1 hour, and the generated phosphorus oxychloride was continuously distilled off. For work-up, the mixture is cooled, 600 ml of ethyl acetate are added, the mixture is poured into ice-water, sodium carbonate is added in portions and made weakly alkaline with cooling, the organic phase is separated off and the aqueous phase is ethyl acetate. Extracted with 300 ml. The combined organic phases were dried over magnesium sulfate, concentrated under vacuum and distilled under a water pump vacuum.

176.8 g (89% of theory) of 3-trichloromethylpyridine having a boiling point of 105 DEG-107 DEG C./15 mbar were obtained.

Stage 2: 31.6 g (0.161 mol) of 3-trichloromethylpyridine
Was added dropwise and with stirring at reflux for 45 minutes to a solution of sodium methoxide in methanol. When the addition is complete, the mixture is stirred at reflux for a further 3 hours, then cooled and filtered, the liquid is concentrated, the residue is taken up in dichloromethane, the mixture is again filtered, the liquid is concentrated and the residue is evaporated in vacuo. Distilled down.

2-methoxy-5 with a boiling point of 54-55 ° C./0.25 mbar
Bis (methoxy) methylpyridine 24.5 g (theoretical 83
%).

Stage 3: 20 ml of concentrated aqueous hydrochloric acid are added to 20 g (0.109 mol) of 2-methoxy-5-bis- (methoxy) methylpyridine in 100 ml of water, the mixture is stirred for 1 hour at room temperature and then cooled to 0 ° C. Aspirated and separated.

12.9 g (82% of theory) of 6-methoxypyridine-3-aldehyde having a melting point of 47-49 ° C. were obtained.

Stage 4: To 10.9 g (0.08 mol) of 6-methoxypyridine-3-aldehyde in 100 ml of ethanol was added 2 g of Raney nickel, followed by hydrogenating the mixture at 75 ° C. and 50 bar hydrogen pressure for 3 hours. For treatment, the catalyst was separated off and the liquor was concentrated under vacuum.

2-methoxy-5-hydroxy-methylpyridine 11.1
g (100% of theory) were obtained, which was purified by distillation: bp 85-88 ° C./0.6 mbar.

Stage 5: 6.5 g (0.041 mol) of N, N-dibutylformamide are added to 28.6 g (0.206 mol) of 2-methoxy-5-hydroxymethylpyridine in 100 ml of toluene, the mixture is heated to 80 DEG C. and the thin-layer chromatogram ( Silica gel; eluent, petroleum ether / ethyl acetate 5: 1), a phosgene stream was passed slowly through the solution until the starting material was no longer detectable (about 2.5 hours). For the treatment, the excess phosgene is removed by flushing with nitrogen at 80 ° C., then the mixture is cooled to room temperature, water is added, a slightly alkaline pH is added by adding sodium carbonate, and the organic phase is separated off. The aqueous phase was extracted with 50 ml of toluene, the combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure.

2-chloro with a boiling point of 70-80 ° C / 1mm by high vacuum distillation
27.6 g (88% of theory) of 5-chloromethylpyridine were obtained.

Step 2 + Step 3 + Step 4 (one-pot method) 98.3 g (0.5 mol) of 3-trichloromethylpyridine is
It was added dropwise and with stirring at reflux temperature over a period of 25 minutes to a solution of 344 g (1.6 mol) of sodium methoxide in methanol. When the addition is complete, the mixture is heated to the boiling point for a further 5 hours, then cooled to room temperature and 100 ml of water
Is added, and the pH is adjusted to pH 3 by addition of 15 ml of concentrated aqueous hydrochloric acid.
4 was established. The mixture was stirred at room temperature for 14 hours, and then 10 g of palladium-supported active end (pd 10%) was added thereto.
0 ml was added and the mixture was hydrogenated under atmospheric pressure with vigorous stirring. After 3.5 hours (hydrogen absorption: 10.790)
The mixture was neutralized with saturated aqueous sodium bicarbonate solution, filtered, the liquid was concentrated, the residue was taken up in ethyl acetate, the mixture was filtered again, concentrated, and distilled.

52.5 g (76.6% of theory) of 2-methoxy-5-hydroxy-methylpyridine having a boiling point of 85-88 DEG C./0.6 mbar were obtained.

Step 2 + Step 3: (one-pot method) 50 g (0.254 mol) of 3-trichloromethyl-pyridine were added to 32.6 g (0.8%) of sodium hydroxide at reflux temperature for 15 minutes.
15 mol) and 200 ml of methanol. The reaction mixture was refluxed for a further 60 minutes, cooled to 20 ° C. and firstly 100 ml of water and then 25 ml of concentrated hydrochloric acid were added. Mix 2
After refluxing at 0 ° C. for 3 hours, this was concentrated to about 100 ml,
Dilute again with water and extract twice with ethyl acetate. The combined extract solution was dried over sodium sulfate and filtered. The solvent was then carefully removed from the liquor by distillation under a water pump vacuum.

27.2 g (78.5% of theory) of 6-methoxypyridine-3-aldehyde having a melting point of 47-49 ° C. were obtained.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-68565 (JP, A) JP-A-54-115381 (JP, A) JP-A-2-218666 (JP, A) JP-A-2- 292262 (JP, A) JP-B-49-45379 (JP, B2) U.S. Pat. No. 4,211,873 (US, A) Tetrahedron Letters, Vol. 25, p. 5693-5696 (1984) Journal of Heterocyclic Chemistry, Vol. 10, p. 779-784 (1973) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 213/61 CA (STN)

Claims (5)

(57) [Claims] (1) Formula (II) Nicotinic acid with phosphorus pentachloride, if appropriate in the presence of thionyl chloride and, if appropriate, in the presence of a diluent,
Formula (III) obtained by In a second stage, if appropriate in the presence of a diluent, of the formula (IV) R-OM (IV) wherein R represents alkyl and M is an alkali metal cation With an alkali metal alkoxide of formula (V) Wherein R has the meaning given above, in a third step, if appropriate in the presence of a catalytic acid, with water, and then the resulting formula (VI) Wherein R has the meaning given above, in a fourth stage in the presence of a hydrogenation catalyst and, if appropriate, in the presence of a diluent, with hydrogenation with molecular hydrogen, and finally Formula (VII) obtained from Wherein R is as defined above, in a fifth step in the presence of a diluent and, if appropriate, in the presence of a reaction aid, with a chlorinating agent of the formula (I) ) For producing 2-chloro-5-chloromethylpyridine. 2. The method according to claim 1, further comprising the steps of combining steps 2 and 3, or steps 3 and 4, or any combination of steps 2, 3 and 4.
2. The process according to claim 1, wherein the intermediate is directly carried out by a one-step reaction without isolation. 3. A process according to claim 1, wherein steps 2 and 3 are carried out without isolation of the intermediate. 4. The process according to claim 1, wherein steps 3 and 4 are carried out without isolating the intermediate. 5. A process according to claim 1, wherein steps 2, 3 and 4 are carried out without isolation of the intermediate.